Project Abstract It is estimated that 4.3 million people in the United States abuse prescription opioids (Center for Behavioral Health Statistics and Quality (CBHSQ) 2015) and that these are the second most abused illicit drugs by youths between the ages of 12 and 17. The long-term consequences of adolescent prescription opioid abuse on subsequent drug use in adulthood are unknown. Further, the underlying mechanism(s) associated with these behaviors are not known. Susceptibility of the adolescent brain to environmental insult is due, in part, to the massive neuronal reorganization and growth that occurs during this time. Recent studies have identified epigenetic regulation of several key genes as major contributors to adolescent neuronal development. Using tractable mouse models, we have evidence that adolescent oxycodone exposure augment morphine reward later in adulthood , and this is associated with changes in gene expression in the dopamine reward pathway. We will validate and extend these preliminary findings and identify potential underlying mechanisms by analyzing the epigenetic regulation of target gene expression as well as genome-wide histone post-translational modifications.